EP2547663A1 - Procédé de préparation d'ambrisentan très pur - Google Patents

Procédé de préparation d'ambrisentan très pur

Info

Publication number
EP2547663A1
EP2547663A1 EP10725507A EP10725507A EP2547663A1 EP 2547663 A1 EP2547663 A1 EP 2547663A1 EP 10725507 A EP10725507 A EP 10725507A EP 10725507 A EP10725507 A EP 10725507A EP 2547663 A1 EP2547663 A1 EP 2547663A1
Authority
EP
European Patent Office
Prior art keywords
ambrisentan
reaction mass
solution
preparation
ethyl acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10725507A
Other languages
German (de)
English (en)
Inventor
Amala Kompella
Kali Satya Bhujanga Rao Adibhatla
Veera Swamy Balina
Srinivasu Kasa
Venkaiah Chowdary Nannapaneni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Natco Pharma Ltd
Original Assignee
Natco Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of EP2547663A1 publication Critical patent/EP2547663A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to an improved and novel process for the preparation of highly pure (>99.8%) (+)-2(S)-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3- diphenylpropionic acid (Ambrisentan) of formula-I
  • Ambrisentan which is (+)-2(S)-(4,6-Dimemylpyrimidin-2-yloxy)-3-methoxy-3,3- diphenylprOpionic acid having the formula - 1 is approved under the trademark "Letairis” by the US Food and Drug Administration for the treatment of Pulmonary artery hypertension(P AH) .
  • methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate (II) is dissolved in DMF and sodium hydride is added. The mixture is stirred for a hour and then 4,6- dimethyl-2-(methylsulfonyl)pyrimidine is added. After stirring at room temperature for 24hours cautious hydrolysis is carried out with water , the pH is adjusted to 5 with acetic acid. , and the solvent is removed under high vacuum. The residue is taken up in ethyl acetate, washed with water and the solvent is distilled out. The residue is mixed with ether and the resulting precipitate is filtered off.
  • step-2 the step-1 product is hydrolyzed in IN KOH solution in dioxane medium at reflux temperature. After reaction completion the reaction mass is washed with ethyl acetate to remove unreacted ester. The pH of the aqueous layer is adjusted with coned. HCl pH 1-2 and extracted with ethyl acetate. After water washing, ethyl acetate is distilled off and the product was liberated by the addition of ether/hexane mixture.
  • the above process adds two more steps to the Route of synthesis viz., esterification and hydrolysis
  • DMF is added dropwise to a suspension of sodium hydride in DMF. The mixture is stirred for an hour and then 4,6-dimemyl-2-memylsulfonylpyrirnidine in DMF is added.
  • mole ratio of S- 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid , 4,6- dime&yl-2-memylsulfonylpyrimidine and sodium hydride is 1:1.3:3.0 .
  • the objective of this invention is to prepare highly pure Ambrisentan through acid addition salts (l:l)of Ambrisentan.
  • Ambrisentan of higher purity results.
  • the main object of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) Ambrisentan
  • Another object of the invention is to provide a process for preparation of salts of Ambrisentan with S(-)4-nitro phenyl ethyl amine or S(-)-phenyl ethyl amine in high purity(>99.8%).
  • Ambrisentan is prepared by .
  • Treating Ambrisentan with S(-)4-nitro phenyl ethylamine or S(-)-phenyl ethyl amine yielding the corresponding addition salt of Ambrisentan iii.
  • the present invention provides the following process for the ⁇ preparation of Ambrisentan
  • the reaction mass is maintained at 25-30°C for 16-17hours
  • aqueous layer pH is adjusted with IN hydrochloride solution to 2-3 during 30-45 minutes
  • reaction mass is maintained under stirring for 2hours at RT
  • reaction mass temperature is raised to reflux
  • reaction mass is maintained at reflux temperature for 1 hours
  • reaction mass is brought to room temperature and maintained at the same
  • Ambrisentan S-(-)4-nitro phenyl ethyl amine /S(-)-phenyl ethyl amine acid addition salts(l .l) are novel and are identified and characterized by chemical analysis, IR, NMR & Mass spectral. Ambrisentan acid addition salts are further converted to Ambrisentan as follows : i. Ambrisentan S-(-)4-nitro phenyl ethyl amine or S(-)-phenyl ethyl amine addition salt is acidified with diluted hydrochloric acid
  • reaction mass is maintained at room temperature for 2-3hours
  • Example- 1 Process for the preparation highly pure Ambrisentan of the formula -I
  • Step-1 Condensation of S(+) 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid 4,6-dimethyl-2-(-(methylsulfonyl)pyrimidine in DMF medium
  • DMF(400ml) and S-2-Hydroxy-3-mehoxy- 3,3-diphenyl propionic acid(50g) were, charged and stirred for 30 minutes.
  • sodium hydride(18.9g) was added slowly for lhour and reaction mass was maintained at room temperature for one hours.
  • Step - II Preparation of Ambrisentan S(-)4-nitro phenyl ethylamine addition salt(l:l) : Ambrisentan (60g, purity 99.5%) was dissolved in acetone (900ml) and S-(-)4-nitro phenyl ethyl amine(26.2g) was added to the solution over 30 min . Reaction mass ' ⁇ temperature was raised to reflux and maintained for about l-2hrs. Reaction mass was slowly cooled to room temperature and maintained for about 16-18 hr at the same temperature. The precipitated material was filtered and washed with 200mlof acetone.
  • the product was dried at 60-70°C under vacuum till constant weight.
  • Step - III Preparation of highly pure Ambrisentan from Ambrisentan S(-)P-nitro phenyl ethylamine addition salt (1:1):
  • Ambrisentan .S(-)4-nitro phenyl ethyl amine addition salt(60g) was suspended in DM W water(3L)and stirred for 15minutes.
  • Aqueous IN hydrochloric acid solution(500) was added over a period of 30 min to a pH of 1-2 and maintained at the same temperature for 2-3hours.
  • the precipitated product was filtered and washed with purified water. The product was dried at temperature of 60-70°C till constant weight.
  • Example-2 Process for the preparation highly pure Ambrisentan of the formula -I
  • Step-1 Condensation of S(+) 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and 4,6-dimethyl-2-(-(methylsulfonyl)pyrimidine in THF medium
  • Reaction mass was quenched into DM water (15L) and acidified with diluted hydrochloric acid(600ml). Reaction mass was maintained under stirring for 3hours at room temperature. Filtered compound was dissolved in Ethyl acetate and ethyl acetate layer was extracted with IN sodium hydroxide solution(2L) Sodium hydroxide layer was separated and acidified with IN hydrochloride solution(l .25L) . Reaction mass was maintained under stirring for 2hours . The product of the formula-I was filtered and washed with purified water. It was dried in oven at 60-65 °C
  • Step - II Preparation of Ambrisentan S(-) phenyl ethylamine addition salt(l:l) : Ambrisentan (50g, purity 99.5%) was dissolved in acetone (500ml) and S-(-) phenyl ethyl amine(16.0g) was dissolved in acetone(32ml)added to the solution over 30 min . Reaction mass temperature was raised to reflux and maintained for about l-2hrs. Reaction mass was slowly cooled to room temperature and maintained for about 16-18 hr at the same temperature. The precipitated material was filtered and washed with 200mlof acetone. The product was dried at 60-70°C under vacuum till constant weight. Dry weight : 40g
  • Step - III Preparation of highly pure Ambrisentan from Ambrisentan S(-) phenyl ethylamine addition salt(l :l) :
  • Ambrisentan .S(-) phenyl ethyl amine addition salt(40g) was suspended in DM water(2L)and stirred for 15minutes.
  • Aqueous IN hydrochloric acid solution(330ml) was added over a period of 30 min to a pH of 1-2 and maintained at the same temperature for 2-3hours.
  • the precipitated product was filtered and washed with purified water. The product was dried at temperature of

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un nouveau procédé, amélioré, pour la préparation d'un acide (+)-2(S)-(4,6-diméthylpyrimidin-2-yloxy)-3-méthoxy-3,3- diphénylpropionique (Ambrisentan) de formule (I) très pur (>99,8 %).
EP10725507A 2010-03-15 2010-03-15 Procédé de préparation d'ambrisentan très pur Withdrawn EP2547663A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000153 WO2011114338A1 (fr) 2010-03-15 2010-03-15 Procédé de préparation d'ambrisentan très pur

Publications (1)

Publication Number Publication Date
EP2547663A1 true EP2547663A1 (fr) 2013-01-23

Family

ID=42813438

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10725507A Withdrawn EP2547663A1 (fr) 2010-03-15 2010-03-15 Procédé de préparation d'ambrisentan très pur

Country Status (5)

Country Link
US (1) US20130060031A1 (fr)
EP (1) EP2547663A1 (fr)
KR (1) KR20130054250A (fr)
CA (1) CA2792473A1 (fr)
WO (1) WO2011114338A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103524424A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型vi及其制备方法和应用
CN103524425A (zh) * 2012-07-04 2014-01-22 天津药物研究院 一种安立生坦的晶型v及其制备方法和应用
WO2014139086A1 (fr) * 2013-03-12 2014-09-18 江苏康缘药业股份有限公司 Procédé de préparation d'ambrisentan

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19533023B4 (de) 1994-10-14 2007-05-16 Basf Ag Neue Carbonsäurederivate, ihre Herstellung und Verwendung
DE19933164A1 (de) 1999-07-20 2001-01-25 Basf Ag Neue Carbonsäurederivate mit 5,6 substituiertem Pyrimidinring, ihre Herstellung und Verwendung als Endothelin Rezeptorantagonisten

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011114338A1 *

Also Published As

Publication number Publication date
CA2792473A1 (fr) 2011-09-22
KR20130054250A (ko) 2013-05-24
US20130060031A1 (en) 2013-03-07
WO2011114338A1 (fr) 2011-09-22

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